EP0435298A2 - Dispositif et méthode pour la séparation du sang - Google Patents

Dispositif et méthode pour la séparation du sang Download PDF

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Publication number
EP0435298A2
EP0435298A2 EP90125608A EP90125608A EP0435298A2 EP 0435298 A2 EP0435298 A2 EP 0435298A2 EP 90125608 A EP90125608 A EP 90125608A EP 90125608 A EP90125608 A EP 90125608A EP 0435298 A2 EP0435298 A2 EP 0435298A2
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European Patent Office
Prior art keywords
plasma
blood
region
fibrous structure
fibers
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EP90125608A
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German (de)
English (en)
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EP0435298A3 (en
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David B. Pall
Thomas C. Gsell
Vlado I. Matkovich
Harvey Brandwein
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Pall Corp
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Pall Corp
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Publication of EP0435298A2 publication Critical patent/EP0435298A2/fr
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D39/00—Filtering material for liquid or gaseous fluids
    • B01D39/14—Other self-supporting filtering material ; Other filtering material
    • B01D39/16—Other self-supporting filtering material ; Other filtering material of organic material, e.g. synthetic fibres
    • B01D39/1607—Other self-supporting filtering material ; Other filtering material of organic material, e.g. synthetic fibres the material being fibrous
    • B01D39/1623—Other self-supporting filtering material ; Other filtering material of organic material, e.g. synthetic fibres the material being fibrous of synthetic origin
    • B01D39/163—Other self-supporting filtering material ; Other filtering material of organic material, e.g. synthetic fibres the material being fibrous of synthetic origin sintered or bonded
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/491—Blood by separating the blood components

Definitions

  • This invention relates to devices and methods for separation of components of complex suspensions and, more particularly, of cellular fluids such as blood and, particularly, the separation of plasma from whole blood.
  • the devices and methods of the invention permit efficient and selective separation of blood components, and are particularly useful as diagnostic devices or components thereof.
  • This invention is directed primarily to diagnostic tests applied to blood, which, for example, may be obtained from a drop or two squeezed from a finger prick, or may be blood drawn into an anti-coagulant for test purposes or for transfusion, or any other blood product in which red cells are suspended in plasma or in saline, or in other fluid compatible with red cells.
  • Many of these tests rely on colorimetric or spectrophotometric evaluation of a reaction of a fluid component with one or more specific reagents.
  • Such diagnostic evaluation primarily for different anomalies, has been the focus of increasingly refined clinical techniques and devices.
  • a particularly important and very frequently tested body fluid is blood plasma, most often obtained in hospital practice by venipuncture followed by withdrawal of 5 cc or more of blood, which in turn is spun in a centrifuge. The red cells settle to the tube bottom, leaving the clear plasma in the upper portion.
  • This procedure entails the usual hazards of venipuncture, and is not generally feasible in other than hospital environments.
  • Many test procedures require as little as 5 microliters ( ⁇ L), or about 1/5th to 1/10th of the volume of a drop of blood.
  • the subject invention is addressed to methods and devices which provide convenient and economical means for obtaining 3 to 30 ⁇ L of plasma, and to combinations thereof with the other components of diagnostic devices.
  • the devices and methods in accordance with this invention make it possible to obtain the quantities required for these tests from one or two drops of blood, which is readily and rapidly obtainable, for example in a doctor's office, or by an individual for himself.
  • the specimen so obtained is identical with or differs minimally in composition with that obtained by centrifuging.
  • Polyester fiber mats in which the fibers have not been modified have been used for removing leucocytes from blood and blood products, particularly from packed red cells. In these, the red cells pass through the filter, while a proportion of the white cells are retained. It has been recognized that superior performance is obtained if the fiber diameter is smaller, thereby increasing the area of the fiber surfaces and enhancing white cell removal efficiency. Fibers made by the melt blowing process can be processed into webs with average fiber diameter below three micrometers ( ⁇ m), while the finest conventional process (extruded and drawn) fiber currently available has a diameter of 6 to 7 ⁇ m, hence with less than half the surface area. Melt blown fibers are accordingly preferred for these blood filters.
  • a condition in which no flow occurs is that in which the liquid does not wet the material of which the porous structure is made.
  • a series of liquids can be prepared, each with a surface tension of about 3 dynes/cm higher compared with the one preceding.
  • a drop of each may then be placed on a porous surface and observed to determine whether it is absorbed quickly, or remains on the surface.
  • PTFE polytetrafluoroethylene
  • porous media made using other synthetic resins Similar behavior is observed for porous media made using other synthetic resins, with the wet-unwet values dependent principally on the surface characteristics of the material from which the porous medium is made, and secondarily, on the pore size characteristics of the porous medium.
  • fibrous polyester specifically polybutylene terephthalate (hereinafter "PBT") sheets
  • PBT polybutylene terephthalate
  • the CWST of a porous medium may be determined by individually applying to its surface, preferably dropwise, a series of liquids with surface tensions varying by 2 to 4 dynes/cm, and observing the absorption or non-absorption of each liquid.
  • the CWST of a porous medium in units of dynes/cm, is defined as the mean value of the surface tension of the liquid which is absorbed and that of a liquid of neighboring surface tension which is not absorbed.
  • the CWST's were respectively 27.5 and 52 dynes/cm.
  • CWST a series of standard liquids for testing are prepared with surface tensions varying in a sequential manner by 2 to 4 dynes/cm. Ten drops of each of at least two of the sequential surface tension standard liquids are independently placed on representative portions of the porous medium and allowed to stand for 10 minutes. Observation is made after 10 minutes. Wetting is defined as absorption into or obvious wetting of the porous medium by at least nine of the ten drops within 10 minutes. Non-wetting is defined by non-absorption or non-wetting of at least nine of the ten drops in 10 minutes. Testing is continued using liquids of successively higher or lower surface tension, until a pair has been identified, one wetting and one non-wetting, which are the most closely spaced in surface tension. The CWST is then within that range and, for convenience, the average of the two surface tensions is used as a single number to specify the CWST.
  • red cells In packed red cells, as well as in whole blood, the red cells are suspended in blood plasma, which has a surface tension of 73 dynes/cm. Hence, if plasma is placed in contact with a porous medium, spontaneous wetting will occur if the porous medium has a CWST of 73 dynes/cm or higher.
  • the surface tension of the red cell surfaces is given in the literature as 64.5 dynes/cm.
  • the hematocrit of blood i.e. the percent by volume of the blood occupied by the red cells, generally ranges from 37 to 54%, and this concentration is sufficient to cause whole blood to wet porous media with CWST values above 64 to 65 dynes/cm.
  • Figure 1 is a schematic side view of a test apparatus used in certain of the examples.
  • Figure 2 is a schematic side view of a device in accordance with the invention shown in cross section.
  • Figure 2A is a top view of the device shown in Figure 2.
  • FIG. 3 is a perspective of another device in accordance with the invention.
  • Figure 4 is a perspective view of still another device in accordance with the invention.
  • Figure 5 is a side view in cross section of a device for cutting a disc out of a medium useful in the subject invention.
  • Figure 6 is a side view in cross section of a device for forming the disc into the desired shape.
  • Figure 7 is a side view in cross section of the disc after formation into the desired shape of a cupped disc.
  • Figure 8 is a side view in cross section of a cupped disc as shown in Figure 7 positioned in a plastic tube, the combination being a device in accordance with the subject invention.
  • Figure 9 is a side view in cross section showing a variant of the cupped disc of Figure 7, a cupped disc with a flat lower surface.
  • Figure 10 is a side view in cross-section showing a variant of the cupped disc of Figure 9 with a membrane guard layer positioned across the lower side.
  • Figure 11 is an enlarged view of the cupped disc of Figure 10 permitting the membrane layer to be more readily seen.
  • Figure 12 is a side view in cross section showing the cupped disc of Figures 10 and 11 assembled to a second membrane disc.
  • Figure 13 is a side view in cross section showing the cupped disc of Figures 10 and 11 assembled into a plastic tube.
  • the present invention provides a device for separating plasma from blood comprising a synthetic polymeric fibrous structure having a CWST in excess of 65 dynes/cm, the structure having a first region for receiving a blood sample and a second region for accumulating plasma.
  • the invention further provides a method for separating plasma from blood comprising contacting the blood with the fibrous structure of this device.
  • the present invention provides a self-contained device for the separation of plasma from blood comprising a fibrous structure having a form contained within two substantially parallel spherical surfaces intersected by a cylinder.
  • the invention also provides a method for separating plasma from blood comprising contacting the blood with the fibrous structure of this device.
  • the present invention provides a device for separating plasma from blood comprising a fibrous structure in which organic fibers have been grafted to present hydroxyl groups at the filter surfaces, the device having a first region for receiving a blood sample and a second region for accumulating plasma.
  • the invention also provides a method for separating plasma from blood comprising contacting the blood with the fibrous structure of this device.
  • the present invention provides a device for separating plasma from blood comprising a synthetic polymeric fibrous structure having a CWST in excess of 65 dynes/cm, and a V f of >0.2 cc/cc, the structure having a first region for receiving a blood sample and a second region for accumulating plasma.
  • the invention also provides a method for separating plasma from blood comprising contacting the blood with the fibrous structure of this device.
  • the present invention provides a device for separating plasma from blood comprising a fibrous structure having a CWST in excess of 65 dynes/cm, the structure having a first region for receiving a blood sample, a second region for accumulating plasma, and a porous guard layer cooperatively arranged with the second region to allow passage of plasma and prevent passage of red blood cells.
  • the invention also provides a method for separating plasma from blood comprising contacting the blood with the fibrous structure of this device.
  • the present invention also provides a self-contained device for separating plasma from blood and carrying out a diagnostic test comprising a fibrous structure preferably having a CWST in excess of 65 dynes/cm, the structure having a first region for receiving a blood sample, a second region for accumulating plasma, and a porous guard layer cooperatively arranged with the second region to allow passage of plasma and prevent passage of red blood cells, the porous guard layer also serving as a diagnostic medium.
  • the present invention also provides a method for separating plasma from blood comprising contacting the blood with the fibrous structure of this device.
  • the present invention provides a self-contained device for separating plasma from blood and carrying out a diagnostic test comprising a fibrous structure having a CWST in excess of 65 dynes/cm, the structure having a first region for receiving a blood sample, an outwardly extending second region for accumulating plasma, a portion of the first region adjacent to the outwardly extending portion having been compressed to greater density, cooperatively arranged to allow passage of plasma and prevent passage of the red blood cells, the second region serving optionally as a diagnostic medium.
  • the present invention also provides a method for separating plasma from blood comprising contacting the blood with the fibrous structure of this device.
  • the present invention provides a method for separating plasma from blood comprising contacting a first region of a synthetic polymeric fibrous structure having a CWST in excess of 65 dynes/cm with a blood sample.
  • Devices and methods in accordance with the subject invention may be used for separating microliter quantities of plasma from whole blood.
  • a method in accordance with the invention may be used for obtaining clear plasma from quantities of blood of the order of 50 to 100 microliters, whereby the blood is applied to a designated portion of a porous fibrous mat, and a short time thereafter clear plasma appears in another portion of the fibrous mat, from which the plasma can be removed by contacting it with a porous medium of smaller pore size and hence of higher capillarity.
  • the synthetic, polymeric fibrous structures in accordance with the subject invention preferably comprise any of the resins which can be successfully used to form cohesive webs using the melt blowing process. These include polybutylene terephthalate, polyethylene terephthalate, polymethyl pentene, polypropylene, polyethylene, any of a number of polyamides, and polycarbonates, as well as any of a number of less commonly used resins. All fibrous mats made from these polymers have CWST below about 46 dynes/cm, and for use in this invention fibers made therefrom must be surface grafted to raise their CWST to above about 65 dynes/cm, and preferably above 95 dynes/cm, more preferably above 110 dynes per cm.
  • the graft should preferably be such as to produce on the fiber surfaces the highest possible density of hydroxyl groups, mixture of hydroxyl and carboxyl groups, mixture of hydroxyl and methyl groups, or amine groups. In a preferrred process in accordance with this invention, this is accomplished by the use of monomers presenting hydroxyl groups, and polymerizing these in an aqueous environment. Selection of monomers and of conditions for grafting is readily possible for persons familiar with the art. A criterion for selecting webs least likely to remove plasma components is the highest possible CWST. A CWST in excess of 65 dynes/cm, and preferably in excess of 110 dynes/cm, is a criterion for a preferred product of this invention.
  • the melt blowing process for making fibrous webs employs fiberizing nozzles comprising two or more passages, of which the innermost passage delivers softened or molten resin to the tip of the nozzle, while the others deliver a gas, usually air, at high velocity, which attenuates the resin to form fibers.
  • the fibers are then collected and form a web on a moving collector surface usually located about 5 to 25 centimeters from the nozzle tip.
  • the velocity of the moving collector surface should be in excess of about 10 meters/minute. At this collector speed the weight of fiber collected per unit area tends to be small, generally between about one tenth to one hundredth of the thickness required for devices employing a method in accordance with the subject invention, thus up to about 100 layers of medium may be required.
  • the multiple layers produced as described above can be passed through a laminating oven, which may consist of two moving belts which convey the product through an oven, in which pressure rolls form the medium to the required density. This operation bonds the layers to form a single integral sheet, which can then be cut to the required sizes for use in a plasma separating device in accordance with the subject invention.
  • Surface grafting to the desired condition can be done either before or after laminating.
  • Layups can also be preformed to form laminated sheets by compressing between hot platens. Heated dies may be used to obtain special shapes, and to vary the pore size between adjacent areas.
  • Multilayer mats of fiber diameter under about 3 ⁇ m can also be cold formed, with a somewhat lesser degree of adhesive integrity, which is nevertheless sufficient for some applications.
  • the basic function of the media used in the process of the subject invention is to deliver to one section of the porous medium clear plasma derived from another section which has been contacted by blood.
  • media in accordance with this invention comprise first and second regions, a first region where blood is applied and a second region where plasma is concentrated during the separation process via a plasma front advancing ahead of the red cell boundary.
  • the media is secured to a holder for facile manipulation of the media, e.g., during contacting of the second region where the plasma is concentrated with another medium such as a membrane for carrying out a diagnostic test.
  • the subject invention is also directed to such combinations.
  • the device may optionally include an extension portion attached to the edge of the device, thus providing a handle for manipulating the device after it has been wetted by blood.
  • an extension portion attached to the edge of the device, thus providing a handle for manipulating the device after it has been wetted by blood.
  • the end of a polyethylene strip may be melted, and the molten end contacted to the edge of the cup or device, providing, after the molten resin has cooled and become solid, a convenient handle whereby the cupped disc can be manipulated into place prior to use, and removed after use while avoiding contact of the user's fingers with the red cells and plasma.
  • the plasma so concentrated can be used in a number of ways. It can be subjected to a diagnostic test as it is collected, for example by preplacing a reagent in the plasma separating medium, and observing for example a change in color of the collected plasma. Alternately, the plasma collecting area can be placed in contact with one or more hydrophilic filters or membranes of pore size smaller than that of the plasma separation device, whereby the plasma wicks onto the membrane(s), generating a color or other signal on the membrane.
  • the membrane(s) may have been pretreated, for example, with antibodies.
  • the membrane(s) may be placed in contact with an absorbent pad, or placed over an evacuable chamber, allowing water or an aqueous reagent solution to wash, or to react with the contents of the membrane.
  • the plasma separation device used independently of the membrane.
  • Exemplary devices are illustrated in Figures 2, 3, 7, 8 and 9.
  • Blood is placed at one end of the device, and the red cells and plasma migrate to the opposite end, which may project slightly. A portion of the plasma advances ahead of the red cell boundary as the fluids advance toward the opposite end until the red cell boundary is observed to stop, signalling that the section of the filter beyond the red cell boundary has been filled with plasma.
  • the plasma end may then be placed in contact with a membrane, whereby the plasma is rapidly absorbed by the membrane.
  • the time span between application of blood and the completion of saturation of the membrane is less than about one minute.
  • This mode is particularly advantageous because of its convenience; the same separator-applicator device can be used with membranes of a range of sizes and with varied pretreatment.
  • a second advantage is that the progress of the red cell boundary can be observed visually, and the device removed to prevent red cells from reaching the membrane.
  • a third advantage is that the blood containing applicator can be discarded while tests continue on the membrane - a not negligible advantage in view of the current prevalence of blood transmitted diseases.
  • V f has been used to represent the ratio of the volume of the fibers to the volume of the filter mat.
  • the use of this term to characterize the mat is more meaningful than the use of density, especially when comparing media made using fibers of differing densities.
  • PBT web used in the examples was made by melt blowing and collecting the fibers as a web.
  • the web was grafted using Cobalt 60 radiation with, unless otherwise noted hydroxyethyl methacrylate (HEMA) as the monomer, in an aqueous milieu, the product after washing and drying having a fiber diameter of 2.6 ⁇ m, an estimated density of 1.36 g/cc, and a weight of .00138 grams/square centimeter (g/cm2).
  • HEMA hydroxyethyl methacrylate
  • a test apparatus was constructed of transparent plastic as shown in Figure 1, in which the top plate 1 was 2.5 cm wide, 8 cm long and about 1.5 cm thick, and provided a flat surface 2 .
  • the mating member 3 provided an opposed flat surface 4 which is 3 cm wide.
  • example 1a seven layers of the .00138 g/cm2 web were laid one on the other, and strips were cut parallel to the fiber orientation to 0.44 cm wide x 2.58 cm long.
  • the strip 6 was placed on surface 4 perpendicular to the length of the apparatus of Figure 1, and the spacing of the two plates adjusted by means of the two screws 7 (the second not shown) to compress the strip 6 to .054 cm.
  • Blood was then added from a pipet at 5 , while observing the motion of the red cell and plasma boundaries through a reticle equipped microscope. When the red cell boundary became stationary, indicating that all of the pores of the test strip had been filled, the position of the red cell boundary was recorded.
  • the specimen thickness was adjusted to .054 cm. Based on the known fiber weight, the fiber density, and the specimen volume, the ratio of fiber volume to total volume, V f , is 0.13 cc/cc. Multiplying the specimen length by its width and thickness yields the total specimen volume, and multiplying that figure in turn by (1 - V f ) yields the volume of voids in the specimen, which is .0205 cc, or 20.5 ⁇ L. This volume can be assumed to be equal to the volume of blood supplied to the specimen. The volume of plasma collected (2.2 ⁇ L for example 1a) divided by the volume of blood supplied and multiplied by 100 yields the plasma recovery efficiency of 10.8%. Examples 1b to 1g were run in similar fashion, with the appropriate number of layers of the web used for each.
  • Webs with lower V f values have lower efficiency, and for this reason are less preferred. Webs with V f values in excess of 0.20 are preferred, while webs with V f greater than 0.24 are more preferred.
  • Example 2 was performed in the manner of and using the materials and the apparatus of Example 1, and serves to compare the serum separation behavior of otherwise equal strips when cut such that the flow direction is parallel with or perpendicular to the direction of fiber orientation. The results are shown in Table 2.
  • Example 3 describes the production of a plasma separator oriented to obtain parallel flow.
  • the working element 1 at the center of the device shown in schematic elevation in Figure 2 is, like the filter medium of example 1, a multi-layer of fibrous web.
  • CWST is selected to be in a preferred range.
  • the preferred CWST range is >110 dynes/cm, which can be achieved by grafting using monomers such as HEMA, hydroxyethyl acrylate, hydroxylpropyl acrylate, or other hydroxyl presenting monomer(s).
  • the working element 1 is enclosed in a preferably clear plastic sheath 2 of oval cross section in the view perpendicular to the plane of the paper, i.e., see Figure 2A, and is shaped such as to provide a recess 3 into which up to about 150 ⁇ L of blood can be placed.
  • the plastic sheath may have a rectangular or other cross section configuration.
  • the device may then be manually contacted at its projecting lower end 4 to a hydrophilic finely porous member, for example nylon 66 membrane, causing the plasma collected at the lower end of the device to be drawn into the membrane.
  • the membrane may or may not have been pretreated with a reagent which interacts with a component of the plasma, and is generally useful for diagnostic purposes.
  • Example 4 describes a hot formed integral porous element. Seventeen layers of the HEMA grafted PBT web described above were hot compressed at 120° C to a thickness of .064 cm and a V f value of 0.27. A test specimen was then cut from the laminate with its length parallel to the fiber orientation to obtain an integral self bonded strip 0.437 cm wide by 2.6 cm long shown in perspective as item 1 in Figure 3. The strip 1 was then bonded by double sided pressure sensitive tape to a polyester film backing 2 . Blood was placed at 3 in contact with the end of the strip 1, and plasma separation observed in the manner described in example 1. Average volume of plasma collected was 5.7 ⁇ L, average efficiency was 27.7%, and average time to cessation of flow was 163 seconds.
  • Example 5 describes the production of a parallel flow plasma separation device with integral diagnostic capability.
  • Melt blown web made with fiber diameter in the preferred range under 3 ⁇ m is grafted to obtain one of the preferred ranges of CWST, and then may be used as one or more layers with a total weight of .02 grams/cm2 by hot compressing between formed platens to obtain the contour for the test strip 1 shown in Figure 4, the thicker section being about .064 cm thick and 0.5 to 1 cm long, and the thinner section about .042 cm thick x 0.5 cm long.
  • the two sections thus have V f values respectively of about 0.27 and 0.41 cc/cc.
  • the test strip 1 is bonded to a plastic backing 2 in the manner of example 4.
  • Section 4 which may or may not have been preimpregnated with a diagnostic reagent, is used for diagnostic purposes.
  • the thinner, more dense section of the hot compressed preform (test strip) of example 5 is preimpregnated with a reagent, whose purpose is to interact with blood plasma to provide diagnostic information.
  • Example 7 describes an economical and easy to use plasma separating device.
  • Melt blown fibrous web was prepared with a fiber diameter of 2.4 ⁇ m at a weight of .0013 grams per cm2. After ⁇ -grafting with HEMA monomer, washing and drying, CWST was greater than 110 dynes/cm, fiber diameter was 2.6 ⁇ m, and weight was .00138 g/cm2. Sixty-four layers of this medium were laid one on the other and hot compressed between steel platens heated to 120°C to a thickness of 0.27 cm.
  • a steel hollow cylinder “hold down” 1 about 3 cm outside diameter, 1 cm inside diameter and 3 cm long was used to lightly compress the porous medium 2 while the sharpened end of a cylindrical cutting tool 3 of inside diameter 0.794 cm and outside diameter .965 cm was inserted into the 1 cm inside diameter of hold down 1 and rotated to cut a disc 0.794 cm diameter.
  • the disc 4 was then transferred as shown in Figure 6 to a second steel hollow cylinder 5 of inside diameter .797 cm and length about 3 cm.
  • a steel rod 6 of outside diameter 0.795 cm was formed at one end to a convex 0.476 cm spherical radius, and a second such rod 7 was formed at one end to a concave 0.476 cm spherical radius.
  • the two rods were inserted into the 0.797 cm diameter cylinder 5 , and a force of 11 Kg was applied to the rod ends to form the disc 4 into a cup shaped member.
  • the product is shown in vertical cross section as item 8 in Figure 7, in which the cross sectioned (hatched) portion represents fiber, while the unshaded upper portion represents a near to hemispherical receptacle into which 2 or 3 drops of blood can be placed.
  • the cupped disc 8 had an outer diameter about .01 cm larger than the 0.797 cm diameter cylinder within which it was formed, and the fibrous (shaded) portion was about 0.25 cm thick. Cohesive strength was more than adequate to withstand the manipulation incident to the procedures described below.
  • the cupped disc was placed with its convex lower surface down on a 1.5 cm square of porous nylon 66 membrane which had been pretreated to bind organic molecules such as antibodies, enzymes, peptides, nucleic acids, and carbohydrates.
  • 120 ⁇ L of blood was placed on the concave upper surface of the cupped disc; within about one minute, the treated nylon disc was saturated with clear plasma to a diameter of 1.3 cm.
  • the upper 90% of the cupped disc was seen to be saturated with red cells, while the bottom 10% remained white, being saturated with clear plasma.
  • cupped disc 8 An understanding of the advantages of the cupped disc 8 may be obtained by comparing it with a simple right circular disc used for the same purpose:
  • the three step process described above in which a laminate is hot formed, then cut to disc form, then shaped to form a cup, may be combined into one by first preheating the layup, for example by passing hot air through it, and while still hot, cutting a disc and sequentially in the same operation compressing and forming the finished cupped disc.
  • a stronger, more coherent cupped disc, more resistant to mechanical damage during storage, shipping and use, can be obtained by modifying the procedure of example 7 as follows: (a) The fibers of the melt blown web are surface grafted, and the web is then water washed, (b) the wet web is laid up and processed to form a cupped disc as described in example 7, (c) the formed cup is then dried by application of heat thereto.
  • example 7 flow is perpendicular to the fiber orientation.
  • shape of the device of this embodiment may be described as "contained within two parallel (not concentric) spherical surfaces intersected by a cylinder", however, it should be understood that minor deviations from parallelism fall within the purview of this embodiment of the invention.
  • Example 8 describes a variant of Example 7. As shown in Figure 9, this variant is distinguished by presenting a flat lower surface. This is advantageous when the device is used for its intended function, as it will deliver plasma faster, and provide a better yield of plasma, while at the same time providing a receptacle for the applied blood as does example 7.
  • Example 9 The devices of example 7 incorporating two reagents.
  • Diagnostic procedures often require that a first reagent be added to the plasma before it contacts a second reagent, the second reagent having been covalently or ionically bonded for example, to a finely porous polyamide membrane in a pretreatment step.
  • a first reagent be added to the plasma before it contacts a second reagent, the second reagent having been covalently or ionically bonded for example, to a finely porous polyamide membrane in a pretreatment step.
  • eight layers of the 1.2 mg/cm2 HEMA grafted melt blown web are pretreated by saturation with a solution of the first reagent, and then allowed to dry.
  • HEMA grafted melt blown web 56 layers of HEMA grafted melt blown web are hot compressed at 120°C to a thickness of about 0.28 cm, and the two portions are then combined and formed to a cup shape as described in example 7 (Figure 7), or to the flatter configuration of example 8 ( Figure 9), with the impregnated portion on the lower face.
  • the proportion of pretreated layers may vary from zero to 100%, and 10 to 100 total layers may be used.
  • Hot compression can be performed in the range of 120° to 170°C, thickness of the device may vary from 0.15 to 0.35 cm, and the pretreated layers may vary from 5 to 50% of the total thickness.
  • the first reagent dissolves in the plasma as it diffuses through the lower portion of the device, and then contacts the second reagent in the membrane, providing a diagnostic signal, such as a color change, of the membrane.
  • both the first and second reagents may be contained in the device in successive layers, and the product of the resulting reaction is adsorbed by a membrane, providing a diagnostic signal.
  • Example 10 Making an enclosed cupped plasma separating device: As shown in Figure 8, a cupped disc 8 made as described in example 7 was ejected from the second steel cylinder 5 of Figure 6 directly into a plastic tube 2 of inside diameter 0.79 cm and outside diameter 0.95 cm. The tube comprised an internal flange at its lower end, which served to locate the disc such that its convex lower surface projected from the bottom of the tube, as shown in Figure 8. The 2 cm length of the tube 2 permitted it to be easily grasped by the thumb and forefinger.
  • the device of Figure 8 provides a more rugged test assembly, requires less care in packaging and during storage and use, speeds up the test process, and obviates the need for tweezers to manipulate the separation device of example 7. Still another advantage of this device is that the blood may be conveniently delivered to the disc by using standard microhematocrit (MH) tubes.
  • the MH tube is filled by contacting it to blood oozing from a finger prick, and placed in the plastic tube with its end in contact with the cupped disc, where it then rests freely at a small angle from vertical until emptied by the capillarity of the disc.
  • the same MH tube, or another, may if necessary then be refilled to obtain the required quantity of plasma in the membrane.
  • cupped disc obviates the need for a leak tight seal to the tube wall, as would be needed with a simple right circular disc.
  • a further advantage is that the cup shape provides secure retention in an internally flanged cylinder; a simple disc used with a flange would not contact an underlying membrane. If the cup is such that its outer diameter is near to vertical at the rim, it may be provided with an outwardly extending flange, which in assembly serves to retain the cup in the plastic tube.
  • Example 11 is a cupped plasma separating device with an abrasion resistant lower surface.
  • the device of example 8 ( Figure 9) is made with the application to the lower face of a thin flexible relatively more abrasion resistant porous layer of higher density, which may for example be made by hot calendering melt blown web, or by using a woven or non-woven fabric.
  • the applied layer is preferably hydrophilic and more preferably has a CWST in excess of 110 dynes per cm.
  • Example 12 describes the characteristics of 2.4 ⁇ m fiber diameter PBT melt blown web grafted with monomers which present surface groups other than hydroxyl. Test strips of these media were prepared at the same weight and V f as example 1d, and were tested in the manner of example 1d.
  • Example 12a was grafted to present a mixture of carboxyl and hydroxyl groups, and tested in the sodium salt form. It had a CWST of 96 dynes/cm; the best of several results obtained had an average separation efficiency of 14.3%.
  • Example 12b grafted to obtain fibers presenting an amine group had a CWST of 75 dynes/cm, and an average efficiency of 15.7%.
  • Example 12c grafted to obtain fibers presenting hydroxyl groups together with a predominant number of methyl groups, had a CWST of 66 dynes/cm, and an average efficiency of 15.6%.
  • the separation device remove negligibly small quantities of normal or abnormal components from blood. This is preferably accomplished by the devices in accordance with the subject invention which have been grafted to present densely packed hydroxyl groups at the fiber surfaces, and which have CWST greater than 110 dynes/cm.
  • BSA bovine serum albumin
  • the test is run using radioactively labelled BSA as follows: A solution containing 0.1 mg/ml of unlabelled BSA and about 105 cpm/ml 125I-labelled BSA is prepared in a phosphate buffered saline (PBS) solution contained 0.2 grams per liter of monobasic sodium phosphate and 8.77 grams per liter sodium chloride in deionized water.
  • PBS phosphate buffered saline
  • a sample of a porous test medium is placed in a syringe-type filter holder.
  • Fluid communication between a reservoir holding the BSA test solution and the syringe-type filter is provided by a length of TygonTM (a trademark of Norton Company) tubing and a peristaltic pump arranged in series.
  • TygonTM a trademark of Norton Company
  • any non-specific protein binding sites present on both the tubing and the filter holder are equilibrated by recirculating 1.0 ml of the BSA solution through the tubing and filter holder at a flow rate of 0.3 ml/min for a period of 15 minutes.
  • the BSA solution is drained from the tubing and filter holder. Residual BSA solution is removed from the tubing and filter holder by circulating about 2.0 ml of PBS through the tubing and filter holder at a flow rate of about 0.3 ml/min for several minutes at ambient temperature.
  • a 13 mm diameter disc of the test medium is assembled into the filter holder whose gasket inner dimension defines a filter area of 0.64 square cm.
  • the 125I-BSA solution is then transferred from the reservoir to the filter holder at a flow rate of 0.8 ml/min/cm2.
  • the test is continued for a period of 5 minutes, during which time 250 micrograms of BSA is passed through the filter holder.
  • a volume of 2.5 cc of PBS is then passed to clear radioactive fluid retained in the disc.
  • the test medium is then removed from the filter holder and blotted dry on filter paper.
  • the amount of protein (BSA) adsorbed by the test disc is determined by radioactive counting in a gamma counter.
  • example 1d Taking into account both plasma recovery efficiency and protein absorption, the product corresponding to example 1d is most preferred, those 12a and 12b are less preferred, and that of 12c still less preferred.
  • Example 14 In like manner to Examples 7 and 9, a plasma separating device having the configuration shown in Figures 10 and 11 was prepared as follows: Sixty-four layers of the medium described in Example 7 were in like manner laid one on the other. A prewet, hydrophilic nylon 66 microporous membrane having a pore size of 0.45 ⁇ m and a thickness of 0.0076 cm was then placed under the layered stack and, using the cutting device shown in Figure 5, a disc 0.794 cm in diameter was cut from the 65 layer stack. The cut disc was then transferred to a forming device similar to that shown in Figure 6 except that the lower steel rod (corresponding to 7 in Figure 6) had an upper surface such as to form the lower surface 4 of the device 1 with a substantially flat form as shown in Figures 10 and 11. Prior to compression under a force of 22.7 Kg, the disc structure was saturated with water by placing about 0.2 cm3 of water in the device.
  • the device 1 was removed from the forming device and dried.
  • the nylon disc conformed to the lower surface of the cupped disc and was firmly bonded thereto.
  • the resulting plasma separation device 1 had the configuration shown in Figure 11 with an upper recess 2 , a bottom membrane layer 3 with a lower or bottom surface 4 .
  • the cupped disc was placed as shown in Figure 12 on a 1.12 cm diameter tared disc of .016 cm thick 0.2 ⁇ m nylon 66 membrane 5 , and 130 microliters of blood was placed in the recess 2 . Within 60 seconds the flow of blood had appeared to cease, with only a small quantity of blood remaining in the recess 2 .
  • membrane layer 3 and disc 5 When put in place prior to the addition of blood, membrane layer 3 and disc 5 were pure white in color; after completion of the test they were still pure white, i.e., no change in color could be observed. This indicates a zero or very low level of hemolysis, and zero passage of red cells through membrane layer 3 .
  • membrane layer 3 serves several purposes.
  • this layer acts as a barrier or guard layer, guarding against the passage of red cells into the region where a diagnostic test may be performed, i.e., either on surface 4 of membrane layer 3 , or on the finer pored nylon disc 5 .
  • Providing a barrier to red cell passage, with no hemolysis, is an important function of the final layer.
  • the guard layer makes the device tolerant of the addition of excess blood, and obviates the need for carefully matching the volume of added blood to the pore volume of the device, thereby making the use of the device easier and faster.
  • the lower surface of the guard layer can itself be used as a diagnostic medium.
  • the membrane guard layer which is non-fibrous, provides abrasion resistance and additional strength in a manner similar to the device described in Example 11.
  • Example 14 While reference is made in Example 14 to the membrane layer 3 as a lower or bottom layer, the use of a layer to provide the benefits described above is not limited to cupped discs and other devices similar in configuration to examples 7, 8, 9, 10, 11, and 14.
  • the tip 4 can be enclosed with a membrane guard layer.
  • the characteristics described above for the membrane layer are best provided by hydrophilic, microporous membranes with pore sizes of from 0.1 to 1.0 micrometer(s).
  • the guard layer is no thicker than about .015 cm, and more preferably is less than .010 cm thick.
  • Nylon 66 membranes are particularly preferred.
  • Other microporous membranes may also be used as well as other porous structures having the requisite characteristics, and are, or have been modified to be wettable by plasma.
  • the guard layer has a larger pore size than a diagnostic medium to which it delivers plasma, as the transfer of plasma is facilitated by the higher capillary attraction of a finer pored diagnostic medium.
  • the plasma contained in the guard layer is "sucked out” into the finer pored layer, to which the plasma is delivered.
  • plasma wicks from the 0.45 ⁇ m guard membrane 3 into the 0.2 ⁇ m diagnostic membrane 5 .
  • Example 15 A flat bottom cupped disc is made in the manner of example 14, except that the membrane disc 3 of Figure 10 has been grafted in the manner described in U.S. Patent No. 4,906,374. A test for removal of blood components is run in the manner of Example 13. The calculated BSA adsorption is increased by less than 2%, an increase within the experimental error of the BSA adsorption test.
  • Example 16 A disc of microporous, hydrophilic nylon 66 membrane, made in accordance with U.S. Patent No. 4,340,479 is processed in accordance with the procedure of U.S. Patent 4,693,985 whereby it becomes capable of readily binding to a variety of proteins, antibodies, and other organic molecules useful in diagnostic procedures.
  • the disc so obtained may then be exposed to a solution of a wide variety of diagnostic reagents, whereby it binds the reagent. When dried, such a disc may be saturated with plasma by substituting it in example 14 for disc 3 and/or disc 5 in Figure 12.
  • Example 17 describes a self contained analytical system for assaying the glucose content of blood.
  • the device of example 14 is modified by (a) pretreating the nylon disc 3 of Figure 10 with tetramethyl benzidine and the enzymes glucose oxidase and horseradish peroxidase, and (b) reducing the quantity of the grafted melt blown web in the device by a factor of 3 to 4 compared with example 14, whereby a single drop of 30 to 60 microliters of blood is sufficient for the test.
  • the blood is placed into the upper recess of the cupped disc, and after about 30 seconds the cupped disc is inverted and exhibits on its nylon face 4 a blue-green color, the intensity of which is proportional to the quantity of glucose present.
  • Similar tests using nylon pretreated with other enzymes and enzyme substrates can be used for quantifying other components of whole blood, for example cholesterol and other lipids, and serum enzymes.
  • Example 18 describes a multi-stage immunological test.
  • Nylon membrane disc 3 of Figure 10 is pretreated with one or more specific antibodies.
  • the cupped disc is then prepared in the manner of example 14, and is shown as item 1 of Figure 13, centrally located within and affixed to a plastic tube (holder) 2 with membrane disc 3 facing downward.
  • a) blood is placed into the recess of the cupped disc 1 , and in less than about 30 seconds the membrane disc 3 becomes saturated with clear plasma; then (b) the tube is inverted, its lower end is connected to a controlled degree of vacuum, and a reagent is added which reacts with one or more components of the plasma bound to the antibody on membrane disc 3 .
  • the procedure is completed by an assay step, which may visually or photometrically evaluate color change, or measure the level of radioactivity, or otherwise evaluate qualitatively or quantitatively the content of the nylon disc.
  • an absorbent pad wettable by water may be placed in the tube in contact with the recess of the cupped disc, such that reagents or washing solutions are absorbed into the pad.
  • Example 19 A standard 96 well microtiter plate containing 96 open bottom holes (known as "wells") is constructed such that each well in the 8 x 12 array terminates in a small inwardly facing flange at its lower end. A 65 layer cupped disc such as that of Example 14 is placed at the bottom of each well, where it is retained by the flange.
  • blood samples can be delivered simultaneously to each of the wells. After 30 to 60 seconds, special equipment available for the purpose can dispense reagents and wash, as well as evaluate and record the results for the 96 specimens of blood. Quite generally, diagnostic tests such as those described in examples 17 and 18 can be performed in multiple using a microtiter plate fitted as noted in this example.
  • plasma separation is accomplished using as a first layer an 11 x 7.5 cm multilayer melt blown web of total weight in the range of .026 to 0.1 g/cm2 and with V f in the range of 0.1 to 0.5 and preferably with a range of 0.2 to 0.38.
  • a second layer consisting of a hydrophilic membrane preferably of pore size 0.1 to 1 ⁇ m and of thickness preferably less than .008 cm, is bonded to the first layer, and the melt blown side of the composite is bonded to the lower end of an injection molded thermoplastic microtiter plate, forming an assembly functionally interchangeable with example 19.
  • a guard layer such as that described in examples 14, 15, 16, 18 and 19 can be applied with advantage to devices in which plasma separation is accomplished by glass fiber.
  • Such a device may incorporate, in addition to the glass fiber mat and a guard layer, a diagnostic membrane which may have been pretreated, and may also be post-treated after exposure to plasma.
  • the guard layer is interposed between the glass fiber mat and the diagnostic membrane, and prevents fouling of the diagnostic membrane by red cells.
  • the guard layer itself may be used as the diagnostic membrane.
  • guard layer is polyhexamethylene adipamide (nylon 66) membrane, which when made by the process of U.S. Patent No. 4,340,479 is hydrophilic as produced
  • other membranes which are not hydrophilic as produced may be used, in some cases to advantage.
  • polytetrafluoroethylene and polyvinylidene fluoride may be used if they are pretreated by grafting or by other means in order to be rendered hydrophilic, and the products so obtained provide the advantage that they are more flexible and more capable of being dimensionally extended than is nylon 66 membrane, hence can be coformed with melt blown webs to a wider range of configurations.
  • membranes which may be used as made, or if necessary to achieve hydrophilicity, after fiber surface modification, include other fluorocarbon resins, those made of nylon resins other than polyhexamethylene adipamide, such as nylon 6, nylon 610, nylon 7, nylon 11 and nylon 12, acrylics, acrylonitriles, polysulfones, polycarbonates, polyphenylene oxide and polyphenylene ether, cellulose, cellulose ester and other cellulose based plastics, acetals, various polyurethanes, various polyesters, silicones, and vinyl chloride.
  • nylon resins other than polyhexamethylene adipamide such as nylon 6, nylon 610, nylon 7, nylon 11 and nylon 12
  • Example 20 A device modified from that described in Example 4 (and illustrated in Figure 3) may be formed from multiple layers of HEMA-grafted PBT web and hot compressed to a described thickness and V f value.
  • the so formed plasma separation medium which, for example, may be fibrous is reduced in length from that shown in Figure 3 such that its length is about one to two times its width and is then bonded, preferably by hot compression, to a porous membrane of length about twice that of the plasma separation medium or about two to four times its width, thus forming a cantilevered portion as a region for accumulating plasma.
  • the plasma flow direction is first downward and generally perpendicular and then generally horizontal through the cantilevered member.
  • a narrow portion of the plasma separation medium adjacent to the cantilevered portion is further compressed to reduce its thickness and increase its density, thereby providing additional assurance that red cells will be prevented from migrating out along the cantilevered membrane.

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EP19900125608 1989-12-28 1990-12-27 Device and method for blood separation Withdrawn EP0435298A3 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0489403A2 (fr) * 1990-12-03 1992-06-10 Pall Corporation Filtre pour système d'infusion
EP0684864A1 (fr) * 1993-12-22 1995-12-06 Baxter International Inc. Procedes de caracterisation de milieux de filtration complexes
WO1998001753A1 (fr) * 1996-07-05 1998-01-15 Amrad Operations Pty. Limited Unite de separation du sang

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5147606A (en) * 1990-08-06 1992-09-15 Miles Inc. Self-metering fluid analysis device
JP2006133143A (ja) * 2004-11-08 2006-05-25 Japan Vilene Co Ltd 血漿又は血清の保持材及び血液分離用具

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2511872A1 (fr) * 1981-08-25 1983-03-04 Messier Denis Dispositif perfectionne pour separer le plasma des globules du sang
EP0313348A2 (fr) * 1987-10-20 1989-04-26 Pall Corporation Dispositif et méthode de déplétion de la teneur en leucocytes du sang et des composants du sang
EP0370584A1 (fr) * 1988-11-23 1990-05-30 Akzo N.V. Filtre et procédé de préparation d'une suspension de trombocytes pauvres en leucocytes
EP0397403B1 (fr) * 1989-05-09 1993-12-22 Pall Corporation Dispositif et méthode de déplétion de la teneur en leucocytes du sang et des composants du sang

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4925572A (en) * 1987-10-20 1990-05-15 Pall Corporation Device and method for depletion of the leukocyte content of blood and blood components
US4880548A (en) * 1988-02-17 1989-11-14 Pall Corporation Device and method for separating leucocytes from platelet concentrate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2511872A1 (fr) * 1981-08-25 1983-03-04 Messier Denis Dispositif perfectionne pour separer le plasma des globules du sang
EP0313348A2 (fr) * 1987-10-20 1989-04-26 Pall Corporation Dispositif et méthode de déplétion de la teneur en leucocytes du sang et des composants du sang
EP0370584A1 (fr) * 1988-11-23 1990-05-30 Akzo N.V. Filtre et procédé de préparation d'une suspension de trombocytes pauvres en leucocytes
EP0397403B1 (fr) * 1989-05-09 1993-12-22 Pall Corporation Dispositif et méthode de déplétion de la teneur en leucocytes du sang et des composants du sang

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0489403A2 (fr) * 1990-12-03 1992-06-10 Pall Corporation Filtre pour système d'infusion
EP0489403A3 (en) * 1990-12-03 1994-05-18 Pall Corp Filter for parenteral systems
EP0684864A1 (fr) * 1993-12-22 1995-12-06 Baxter International Inc. Procedes de caracterisation de milieux de filtration complexes
EP0684864A4 (fr) * 1993-12-22 2000-02-23 Baxter Int Procedes de caracterisation de milieux de filtration complexes
WO1998001753A1 (fr) * 1996-07-05 1998-01-15 Amrad Operations Pty. Limited Unite de separation du sang

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GB2239403B (en) 1994-05-11
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BR9006649A (pt) 1991-10-01
AU6821090A (en) 1991-07-04
EP0435298A3 (en) 1991-11-13
AU640186B2 (en) 1993-08-19
GB2239403A (en) 1991-07-03
CA2032928A1 (fr) 1991-06-29
JPH05312802A (ja) 1993-11-26

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